Côté Jean-François, Kirzin Sylvain, Kramar Andrew, Mosnier Jean-François, Diebold Marie-Danièle, Soubeyran Isabelle, Thirouard Anne-Sophie, Selves Janick, Laurent-Puig Pierre, Ychou Marc
Institut National de la Sante et de la Recherche Medicale UMR-S775, Bases moléculaires de la réponse aux xénobiotiques, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, France.
Clin Cancer Res. 2007 Jun 1;13(11):3269-75. doi: 10.1158/1078-0432.CCR-06-2290. Epub 2007 May 17.
Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial.
Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1.
Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A128 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A11 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005].
This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA>(TA)(7)TAA polymorphism.
伊立替康（CPT - 11）已被批准用于转移性结直肠癌的治疗，但其可导致严重毒性。我们研究的主要目的是在一项前瞻性随机试验中，评估不同基因多态性对接受5 - 氟尿嘧啶（5FU）和CPT - 11辅助化疗方案的高危III期结肠癌患者血液学毒性发生情况及无病生存期的影响。
400例患者被随机分为III期试验，比较LV5FU2与LV5FU2 + CPT - 11。提取184例患者的DNA并进行基因分型，以检测核苷酸多态性：ABCB1的3435C>T、CYP3A5的6986A>G、UGT1A1的UGT1A1*28以及UGT1A1的 - 3156G>A。
两个治疗组的基因型频率相似。在试验组中，ABCB1和CYP3A5基因多态性在毒性或无病生存期方面未观察到显著差异。UGT1A128纯合患者出现严重血液学毒性的频率（50%）高于UGT1A11纯合患者（16.2%），P = 0.06。此外，UGT1A1 - 3156G>A多态性突变等位基因纯合患者出现严重血液学毒性的频率（50%）高于野生型等位基因纯合患者（12.5%），P = 0.01。这种毒性在纯合突变患者中比野生型纯合患者出现得更早（P = 0.043）。在Cox模型中，与G/G基因型患者相比，A/A基因型患者发生严重血液学毒性的风险比显著更高[风险比，8.4；95%置信区间，1.9 - 37.2；P = 0.005]。
本研究支持在LV5FU2 + CPT - 11治疗前鉴定UGT1A1启动子多态性以预测早期血液学毒性的临床实用性。 - 3156G>A多态性似乎比UGT1A1（TA）(6)TAA>(TA)(7)TAA多态性是更好的预测指标。
